4-(2 phenylthiazol-5-yl)-1, 4-diazabicyclo-[3.2.2]nonane derivatives, preparation and therapeutic use thereof

ABSTRACT

Compound corresponding to the general formula (I)                  
 
in which R 1 , R 2 , R 3 , R 4  and R 5  each represent a hydrogen or halogen atom or a nitro, amino, trifluoromethyl, trifluoroalkoxy, cyano, hydroxyl, (C 1 –C 6 )alkyl or (C 1 –C 6 )alkoxy group and R 6  represents a (C 1 –C 6 )alkyl group.
 
     Therapeutic application.

This application is a National Stage entry under 35 U.S.C. §371 ofInternational application No. PCT/FR01/01650 filed May 29, 2001, whichis incorporated herein by reference in its entirety.

The compounds of the present invention correspond to the general formula(I)

in whichR₁, R₂, R₃, R₄ and R₅ each represent, independently of each other, ahydrogen or halogen atom or a nitro, amino, trifluoromethyl,trifluoroalkoxy, cyano, hydroxyl, (C₁–C₆)alkyl or (C₁–C₆)alkoxy group.

The compounds of the invention may exist in the form of bases or ofaddition salts with acids.

In accordance with the invention, the compounds of general formula (I)may be prepared by reacting 1,4-diazabicyclo[3.2.2]nonane, of formula(II)

with a compound of general formula (III)

in which R₁, R₂, R₃, R₄ and R₅ are as defined above, and the aboveproduct is then cyclized in the presence of4-methoxyphenylthionophosphine sulfide dimer (Lawesson's reagent), oralternatively in the presence of2,4-bis(phenylthio)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (cf.Synth. Commun. 1984, 827).

The preparation of 1,4-diazabicyclo[3.2.2]nonane is described in J. Med.Chem. 1993, 36, 2311–2320.

The compounds of general formula (III) are commercially available or areaccessible by methods described in the literature.

The examples that follow illustrate the preparation of a number ofcompounds according to the invention. The elemental microanalyses andthe IR and NMR spectra confirm the structures of the compounds obtained.

The numbers indicated in parentheses in the example titles correspond tothose in the first column of table 1 given later.

In the compound names, the hyphen “-” forms part of the word, and theunderscore line “_” serves merely to indicate the line-break split; itshould be removed if it does not occur at a line break, and should notbe replaced either by a normal hyphen or by a space.

EXAMPLE 1 Compound 14-(2-Phenylthiazol-5-yl)-1,4-diazabicyclo[3.2.2]nonane hydrobromide 1:21.1 N-[2-(1,4-Diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]benzamide

1.06 9 (5.9 mmol) of N-benzoylglycine (hippuric acid) dissolved in 20 mlof chloroform are placed in a 50 ml round-bottomed flask and 2.9 g (17.9mmol) of 1,1′-carbonylbis-1H-imidazole are added, and the mixture isthen stirred at room temperature for one hour.

0.75 g (5.9 mmol) of 1,4-diazabicyclo[3.2.2]nonane dissolved in 5 ml ofchloroform is added and the mixture is stirred for 24 hours.

The solvent is evaporated off under reduced pressure and the residue ispurified by chromatography on a column of silica gel, eluting with a90/10/1 mixture of chloroform, methanol and aqueous ammonia.

1.3 g of product are obtained in the form of an oil.

1.2 4-(2-Phenylthiazol-5-yl)-1,4-diazabicyclo[3.2.2]nonane hydrobromide1:2

1.3 g (4.5 mmol) ofN-[2-(1,4-diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]benzamide dissolved in50 ml of toluene are placed in a 100 ml round-bottomed flask, 1.8 9 (4.5mmol) of 4-methoxyphenylthionophosphine sulfide dimer (Lawesson'sreagent) are added and the mixture is heated at 120° C. for 18 hours.

The solvent is evaporated off under reduced pressure and the residue ispurified by chromatography on a column of silica gel, eluting with a95/5/0.5 mixture of chloroform, methanol and aqueous ammonia. Theproduct obtained is dissolved in isopropyl alcohol and a 33% solution ofhydrobromic acid in acetic acid is added. The crystals obtained (0.14 g)are collected by filtration.

Melting point: 275–277° C.

EXAMPLE 2 Compound 54-[2-(2-Methylphenyl)thiazol-5-yl]-1,4-diazabicyclo[3.2.2]nonanehydrobromide 1:2 2.1N-[2-(1,4-Diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]-2-methylbenzamide

0.47 g (2.28 mmol) of dicyclohexylcarbodiimide dissolved in 20 ml ofdioxane is placed in a 50 ml round-bottomed flask at room temperature.0.4 g (2.07 mmol) of N-(o-toluyl)glycine is then added and the mixtureis stirred for 30 minutes at room temperature.

0.26 g (2.07 mmol) of 1,4-diazabicyclo[3.2.2]nonane dissolved in 5 ml ofdioxane is added and the mixture is stirred for one hour.

50 ml of water are added, the precipitate formed is filtered off and theaqueous phase is extracted with chloroform. The organic phase isextracted with-aqueous 0.1N hydrochloric acid solution and the aqueousphase is basified to pH 10 by addition of concentrated aqueous sodiumhydroxide solution and extracted with chloroform.

The organic phase is dried over sodium sulfate and concentrated underreduced pressure. 0.41 g of product is obtained in solid form.

Melting point: 177° C.

2.2 4-[2-(2-Methylphenyl)thiazol-5-yl)-1,4-diazabicyclo[3.2.2]nonanehydrobromide 1:2

0.41 g (1.36 mmol) ofN-[2-(1,4-diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]-2-methylbenzamidesuspended in 20 ml of xylene is placed in a 50 ml round-bottomed flask,0.611 g (1.5 mmol) of 2,4-bis(phenylthio)-1,3,2,4-dithiadiphosphetane2,4-disulfide is added and the mixture is refluxed for 20 hours.

The solvent is evaporated off under reduced pressure and the residue ispurified by chromatography on a column of silica gel, eluting with a95/5/0.5 mixture of chloroform, methanol and aqueous ammonia.

The product obtained is dissolved in ethanol, a 33% solution ofhydrobromic acid in acetic acid is added and the crystals obtained arerecrystallized from isopropyl alcohol.

0.168 g of product is obtained in solid form.

Melting point: 276–279° C.

EXAMPLE 3 Compound 74-[2-(3-Methoxyphenyl)thiazol-5-yl]-1,4-diazabicyclo[3.2.2]nonaneoxalate 1:1 3.1 N-(3-Methoxybenzoyl)glycine

1.5 g (20 mmol) of glycine dissolved in 20 ml of aqueous 2N sodiumhydroxide solution are placed in a 50 ml round-bottomed flask, themedium is heated to 50° C., 3.1 ml (20 mmol) of 3-methoxybenzoylchloride are added dropwise and the mixture is stirred at 50° C. for 30minutes. It is cooled to room temperature and kept stirring for 20hours.

The reaction medium is cooled to 4° C. and 2 ml of concentrated aqueoushydrochloric acid solution are added slowly. The precipitate obtained iscollected by filtration and recrystallized from toluene.

2.77 g of crystals are obtained.

Melting point: 124° C.

3.2N-[2-(1,4-Diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]-3-methoxybenzamide

0.42 g (2 mmol) of N-(3-methoxybenzoyl)glycine dissolved in 20 ml ofdioxane is placed in a 50 ml round-bottomed flask, 0.45 g (2.2 mmol) ofdicyclohexylcarbodiimide is added and the mixture is stirred at roomtemperature for 30 minutes, 0.25 g (2 mmol) of1,4-diazabicyclo[3.2.2]nonane is added and the mixture is stirred for afurther two hours.

20 ml of water are added, the precipitate formed is filtered off and thefiltrate is extracted with chloroform. The organic phase is extractedwith aqueous 0.1N hydrochloric acid solution and the aqueous extractionphase is basified to pH 10 by addition of concentrated aqueous sodiumhydroxide solution and extracted with chloroform. The organic phase isdried over sodium sulfate-and concentrated under reduced pressure.

0.43 g of product is obtained in the form of an amorphous solid.

3.3 4-[2-(3-Methoxyphenyl)thiazol-5-yl]-1,4-diazabicyclo[3.2.2]nonaneoxalate 1:1

0.42 g (1.32 mmol) ofN-[2-(1,4-diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]-3-methoxybenzamidesuspended in 15 ml of xylene is placed in a 25 ml round-bottomed flask,0.59 g (1.45 mmol) of 2,4-bis(phenylthio)-1,3,2,4-dithiadiphosphetane2,4-disulfide is added and the mixture is refluxed for 20 hours.

Aqueous 0.5N sodium hydroxide solution is added and the aqueous phase isextracted with chloroform. The organic phase is dried over sodiumsulfate and evaporated under reduced pressure, and the residue ispurified by chromatography on a column of silica gel, eluting with a90/10 mixture of ethyl acetate and methanol. The product obtained isdissolved in acetone, a solution of oxalic acid in acetone is added andthe crystals obtained (0.166 g) are collected by filtration.

Melting point: 192–193° C.

EXAMPLE 4 Compound 64-[2-(4-Methoxyphenyl)thiazol-5-yl]-1,4-diazabicyclo[3.2.2]nonaneoxalate 1:1 4.1 N-(4-Methoxybenzoyl)glycine

2.93 g (39 mmol) of glycine dissolved in 41 ml of aqueous 1N sodiumhydroxide solution are placed in a 250 ml round-bottomed flask, themixture is cooled to 4° C., 41 ml of aqueous 1N sodium hydroxidesolution and a solution of 7 g (0.041 mol) of 4-methoxybenzoyl chloridein 10 ml of dioxane are added simultaneously, dropwise over 45 minutes,and the mixture is stirred for 20 hours.

Concentrated aqueous hydrochloric acid solution is added to pH 1 and theprecipitate formed is collected by filtration and recrystallized fromisopropyl alcohol.

3.74 g of product are obtained.

Melting point: 173° C.

4.2N-[2-(1,4-Diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]-4-methoxybenzamide

0.42 g (2 mmol) of N-(4-methoxybenzoyl)glycine dissolved in 20 ml ofdioxane is placed in a 50 ml round-bottomed flask, 0.45 g (2.2 mmol) ofdicyclohexylcarbodiimide is added, the mixture is stirred at roomtemperature for 30 minutes, 0.25 g (2 mmol) of1,4-diazabicyclo[3.2.2]nonane is added and the mixture is stirred for afurther one hour. 20 ml of water are added, the precipitate formed isfiltered off, the filtrate is extracted with chloroform, the organicphase is extracted with aqueous 0.1N hydrochloric acid solution and theaqueous extraction phase is basified to pH 10 by addition ofconcentrated aqueous sodium hydroxide solution and extracted withchloroform. The organic phase is dried over sodium sulfate andconcentrated under reduced pressure.

0.49 g of product is obtained in the form of an amorphous solid.

4.3 4-[2-(4-Methoxyphenyl)thiazol-5-yl]-1,4-diazabicyclo[3.2.2]nonaneoxalate 1:1

0.47 g (1.48 mmol) ofN-[2-(1,4-diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]-4-methoxybenzamidedissolved in 15 ml of xylene is placed in a 25 ml round-bottomed flask,0.66 g (1.63 mmol) of 2,4-bis(phenylthio)-1,3,2,4-dithiadiphosphetane2,4-disulfide is added and the mixture is refluxed for two hours.

The solvent is evaporated off under reduced pressure and the residue ispurified by chromatography on a column of silica gel, eluting with a95/5/0.5 mixture of ethyl acetate, methanol and diethylamine. Theproduct obtained is dissolved in ethanol and a solution of oxalic acidin ethanol is added. The crystals obtained (0.176 g) are collected byfiltration.

Melting point: 219–222° C.

EXAMPLE 5 Compound 84-[2-(3-Bromophenyl)thiazol-5-yl]-1,4-diazabicyclo[3.2.2]nonane oxalate1:1 5.1 N-(3-Bromobenzoyl)glycine

1.5 g (20 mmol) of glycine dissolved in 20 ml of aqueous 2N sodiumhydroxide solution are placed in a 50 ml round-bottomed flask. Themedium is heated to 50° C., 2.6 ml (20 mmol) of 3-bromobenzoyl chlorideare added dropwise, and the mixture is stirred for 30 minutes at thistemperature, cooled to room temperature and stirred for 20 hours.

The reaction medium is cooled to 4° C., 2 ml of concentrated aqueoushydrochloric acid solution are added slowly and the precipitate obtainedis collected by filtration and recrystallized from toluene.

3.21 g of crystals are obtained.

5.2 N-[2-(1,4-Diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]-3-bromobenzamide

0.77 g (3 mmol) of N-(3-bromobenzoyl)glycine dissolved in 30 ml ofdioxane is placed in a 100 ml round-bottomed flask, 0.68 g (3.3 mmol) ofdicyclohexylcarbodiimide is added and the mixture is stirred at roomtemperature for 30 minutes, 0.38 g (3 mmol) of1,4-diazabicyclo[3.2.2]nonane is added and the mixture is stirred for afurther two hours. 30 ml of water are added and the precipitate formedis filtered off, the filtrate is extracted with chloroform and theorganic phase is then extracted with aqueous 0.1N hydrochloric acidsolution. The aqueous extraction phase is basified to pH 10 by additionof concentrated aqueous sodium hydroxide solution and extracted withchloroform. The organic phase is dried over sodium sulfate andconcentrated under reduced pressure.

0.95 g of product is obtained in the form of an oil.

5.3 4-[2-(3-Bromophenyl)thiazol-5-yl]-1,4-diazabicyclo[3.2.2]nonaneoxalate 1:1

0.93 g (2.54 mmol) ofN-[2-(1,4-diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl)-3-bromobenzamidedissolved in 25 ml of xylene is placed in a 25 ml round-bottomed flask,1.14 g (2.79 mmol) of 2,4-bis(phenylthio)-1,3,2,4-dithiadiphosphetane2,4-disulfide are added and the mixture is refluxed for two hours.

The solvent is evaporated off under reduced pressure and the residue ispurified by chromatography on a column of silica gel, eluting with a95/5/0.5 mixture of ethyl acetate, methanol and aqueous ammonia. Theproduct obtained is dissolved in ethanol and a solution of oxalic acidin ethanol is added. The crystals obtained (0.055 g) are collected byfiltration.

Melting point: 161–163° C.

Table 1 below illustrates the chemical structures and physicalproperties of a number of compounds of the invention.

TABLE (I)

No. R₁ R₂ R₃ R₄ R₅ Salt m.p. (° C.) 1 H H H H H HBr 2:1 275–277 2 H HCH₃ H H HBr 1:1 287–290 3 H CH₃ H H H HBr 1:1 272–274 4 H H NO₂ H H HBr1:1 309–313 5 CH₃ H H H H HBr 2:1 276–279 6 H H OCH₃ H H ox. 1:1 219–2227 H OCH₃ H H H ox. 1:1 192–193 8 H Br H H H ox. 1:1 161–163 9 F H H F Hox. 1:1 217–219 10 H H CF₃ H H ox. 1:1 214–217 11 I H H H H ox. 1:1214–217 12 H H OCF₃ H H ox. 1:1 153–155 13 H H Br H H ox. 1:1 214–215 14H OCH₃ OCH₃ H H ox. 1:1 196–198 15 H F F H H ox. 1:1 188–190 16 Cl Cl HH H ox. 1:1 189–191 17 H Cl H Cl H ox. 1:1 224–226 18 H OCH₃ H OCH₃ Hox. 1:1 180–181 19 OH H H H H ox. 1:1 196–197 20 Br H H H H ox. 1:1193–194 Key In the “Salt” column, “HBr” denotes a hydrobromide and “ox.”denotes an oxalate. The acid:base molar ratio is indicated opposite.

The compounds of the invention underwent tests that demonstrated theirvalue as therapeutic substances.

Thus, they were studied as regards their affinity with respect tonicotinic receptors containing the α7 subunit, according to the methodsdescribed by Marks and Collins, Pharmacol. 1982, 22, 554 and Marks etal., Mol. Pharmacol. 1986, 30, 427.

Male OFA rats weighing 150 to 200 g are decapitated, the entire brain isremoved quickly and homogenized using a Polytron™ mill in 15 volumes ofa 0.32 M sucrose solution at 4° C., followed by centrifugation at 1000×gfor 10 minutes. The pellet is discarded and the supernatant iscentrifuged at 8000×g for 20 minutes at 4° C. The pellet is recoveredand homogenized using a Polytron™ mill in 15 volumes of double-distilledwater at 4° C., followed by centrifugation at 8000×g for 20 minutes. Thepellet is discarded and the supernatant and the buffy coat arecentrifuged at 40 000×g for 20 minutes. The pellet is recovered,resuspended in 15 volumes of double-distilled water at 4° C. andcentrifuged again at 40 000×g for 20 minutes, before being stored at−80° C.

On the day of the experiment, the tissue is thawed slowly and suspendedin 5 volumes of buffer. 150 μl of this membrane suspension arepreincubated at 37° C. for 30 minutes, in the dark, in the presence orabsence of the test compound. Next, the membranes are incubated for 60minutes at 37° C., in the dark, in the presence of 50 μl of 1 nM[³H]α-bungarotoxin in a final volume of 250 μl of 20 mM HEPES buffer.The reaction is stopped by filtration through Whatman GF/C™ filterspretreated for 3 hours with 0.05% polyethyleneimine. The filters arerinsed with 2×5 ml of buffer at 4° C. and the radioactivity retained oneach filter is measured by liquid scintigraphy. The nonspecific bindingin the presence of α-bungarotoxin at 1 μM is determined; the nonspecificbinding represents about 60% of the total binding recovered on thefilter. For each concentration of test compound, the percentage ofinhibition of the specific binding of [³H] α-bungarotoxin is determined,followed by calculation of the IC₅₀ value, which is the concentration ofcompound that inhibits the specific binding by 50%.

The IC₅₀ values for the purest compounds of the invention are between0.020 and 0.500 μM.

The compounds of the invention were also studied as regards theiraffinity with respect to nicotinic receptors containing the α₄β₂subunit, according to the methods described by Anderson and ArnericinEur. J. Pharmacol. 1994, 253, 261 and by Hall et al. in Brain Res. 1993,600, 127.

Male Sprague-Dawley rats weighing 150 to 200 g are decapitated, theentire brain is removed quickly and homogenized in 15 volumes of a 0.32M sucrose solution at 4° C., followed by centrifugation at 1000×g for 10minutes. The pellet is discarded and the supernatant is centrifuged at20 000×g for 20 minutes at 4° C. The pellet is recovered and homogenizedusing a Polytron™ mill in 15 volumes of double-distilled water at 4° C.,followed by centrifugation at 8000×g for 20 minutes. The pellet isdiscarded and the supernatant and the buffy coat are centrifuged at 40300×g for 20 minutes. The pellet is recovered, resuspended in 15 ml ofdouble-distilled water and centrifuged again at 40 000×g, before beingstored at −80° C.

On the day of the experiment, the tissue is thawed slowly and suspendedin 3 volumes of buffer. 150 μl of this membrane suspension are incubatedat 4° C. for 120 minutes in the presence of 100 μl of [3H]-cytisine at 1nM in a final volume of 500 μl of buffer, in the presence or absence ofthe test compound. The reaction is stopped by filtration through WhatmanGF/B™ filters pretreated with polyethyleneimine. The filters are rinsedwith 2×5 ml of buffer at 4° C. and the radioactivity retained on thefilter is measured by liquid scintigraphy. The nonspecific binding inthe presence of (−)-nicotine at 10 μM is determined; the nonspecificbinding represents 75% to 85% of the total binding recovered on thefilter. For each concentration of test compound, the percentage ofinhibition of the specific binding of ³H]-cytisine is determined,followed by calculation of the IC₅₀ value, which is the concentration ofcompound that inhibits the specific binding by 50%.

The IC₅₀ values for the purest compounds of the invention are between1.4 and 4 μM.

The preceding results show that the compounds of the invention areselective ligands for the α₇ subunits relative to the α₄β₂ subunits ofthe nicotinic receptor.

The results of the various tests suggest the use of the compounds in thetreatment or prevention of disorders associated with a dysfunction ofthe nicotinic receptors, in particular on the central nervous system.

These disorders comprise cognitive impairment, more specifically memoryimpairment, but also attention impairment, associated with Alzheimer'sdisease, pathological ageing (Age Associated Memory Impairment, AAMI),Parkinsonian syndrome, trisomy 21 (Down's syndrome), Korsakoff'salcoholic syndrome and vascular dementia (multi-infarct dementia, MID).

The compounds of the invention may also be useful in the treatment ofthe motor disorders observed in Parkinson's disease or otherneurological diseases such as Huntington's chorea, Tourette's syndrome,tardive dyskinesia and hyperkinesia.

The compounds of the invention can also constitute a curative orsymptomatic treatment for cerebrovascular accidents and cerebral hypoxicepisodes. They can be used in psychiatric pathologies: schizophrenia,depression, anxiety, panic attacks, compulsive and obsessive behavior.

They can prevent the symptoms due to withdrawal from tobacco, fromalcohol and from various substances that induce dependence, such ascocaine, LSD, cannabis and benzodiazepines.

Accordingly, a subject of the present invention is also pharmaceuticalcompositions containing an effective dose of at least one compoundaccording to the invention, in the form of the base or of apharmaceutically acceptable salt or solvate thereof, and as a mixture,where appropriate, with suitable excipients.

Said excipients are chosen according to the pharmaceutical form and thedesired route of administration.

The pharmaceutical compositions according to the invention may thus beintended for oral, sublingual, subcutaneous, intramuscular, intravenous,topical, intratracheal, intranasal, transdermal, rectal or intraocularadministration.

The unit forms of administration may be, for example, tablets, gelcapsules, granules, powders, oral or injectable solutions orsuspensions, transdermal patches or suppositories. Ointments, lotions,and eye lotions may be envisaged for topical administration.

Said unit forms are dosed to allow a daily administration of from 0.01to 20 mg of active principle per kg of body weight, according to thepresentation form.

In order;to prepare tablets, a pharmaceutical vehicle which may becomposed of diluents such as, for example, lactose, microcrystallinecellulose or starch and formulation adjuvants, for instance binders(polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.), glidants,for instance silica, lubricants, for instance magnesium stearate,stearic acid, glyceryl tribehenate or sodium stearylfumarate, is addedto the active principle, which may or may not be micronized. Wettingagents or surfactants such as sodium lauryl sulfate may also be added.

The preparation techniques may be direct tabletting, dry granulation,wet granulation or hot melting.

The tablets may be plain, coated, for example with sucrose, or coatedwith various polymers or other suitable materials. They may be designedto allow a rapid, delayed or sustained release of the active principleby means of polymer matrices or specific polymers used in the coating.

In order to prepare gel capsules, the active principle is mixed with drypharmaceutical vehicles (simple mixing, dry or wet granulation, or hotmelting) or liquid or semi-solid pharmaceutical vehicles.

The gel capsules may be hard or soft, and uncoated or film-coated, so asto have rapid, sustained or delayed activity (for example for an entericform).

A composition in the form of a syrup or elixir for administration in theform of drops may contain the active principle together with asweetener, preferably a calorie-free sweetener, methylparaben orpropylparaben as antiseptic, a flavor enhancer and a colorant.

The water-dispersible powders and granules may contain the activeprinciple mixed with dispersants or wetting agents, or dispersants suchas polyvinylpyrrolidone, and also with sweeteners and flavor enhancers.

For rectal administration, use is made of suppositories prepared withbinders that melt at the rectal temperature, for example cocoa butter orpolyethylene glycols.

For parenteral administration, aqueous suspensions, isotonic salinesolutions or injectable sterile solutions containing pharmacologicallycompatible dispersants and/or wetting agents, for example propyleneglycol or butylene glycol, are used.

The active principle may also be formulated in the form ofmicrocapsules, optionally with one or more supports or additives, orwith a polymer matrix or with a cyclodextrin (transdermal patches,sustained-release forms).

The topical compositions according to the invention comprise a mediumthat is compatible with the skin. They may be especially in the form ofaqueous, alcoholic or aqueous-alcoholic solutions, gels, water-in-oil oroil-in-water emulsions having the appearance of a cream or a gel,microemulsions or aerosols, or alternatively in the form of vesiculardispersions containing ionic and/or nonionic lipids. These presentationforms are prepared according to the usual methods of the fields underconsideration.

Finally, the pharmaceutical compositions according to the invention maycontain, along with a compound of general formula (I), other activeprinciples that may be useful in the treatment of the disorders anddiseases indicated above.

1. A compound of the general formula (I)

in which R₁, R₂, R₃, R₄ and R₅ each represent, independently of eachother, a hydrogen or halogen atom or a nitro, amino, trifluoromethyl,trifluoroalkoxy, cyano, hydroxyl, (C₁–C₆)alkyl or (C₁–C₆)alkoxy group,in the form of the base or of an addition salt with an acid.
 2. Aprocess for preparing a compound according to claim 1 wherein1,4-diazabicyclo[3.2.2]nonane is reacted with a compound of formula(III)

in which R₁, R₂, R₃, R₄ and R₅ are as defined in claim 1, and the aboveproduct is then cyclyzed in the presence of4-methoxyphenylthionophosphine sulfide dimer (Lawesson's reagent), oralternatively in the presence of2,4-bis(phenylthio)-1,3,2,4-dithiadiphosphetane 2,4-disulfide.
 3. Amethod for the treatment of a disease selected from the group consistingof schizophrenia, Alzheimer's disease, Parkinson's disease, Down'ssyndrome, Korsakoff's alcoholic syndrome, vascular dementia, depression,anxiety, panic attack and obsessive-compulsive behavior, which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 1. 4. A pharmaceutical compositioncomprising a compound according to claim 1, combined with an excipient.